RESEARCH PROJECT 2 ? ABSTRACT Chronic alcohol abuse results in hepatic fibrosis and cirrhosis which is driven by activation of myofibroblasts that synthesize the fibrous scar. Using the experimental model of intragastric (IG) alcohol feeding in mice, we and the others have demonstrated that activated Hepatic Stellate Cells (aHSCs) are the major source of myofibroblasts in alcoholic liver fibrosis. Therefore, aHSCs are the primary targets for antifibrotic therapy. Our central hypothesis is that genome-wide epigenetic changes regulating specific transcription factors determine HSC phenotype in alcohol- induced liver fibrosis in patients and in mice. Our strategy is based on the breakthrough technologies of the past 2 years, which enable us for the first time to perform a) RNA-Seq on individual HSCs to explore the diversity of HSC phenotypes in human alcoholic liver disease (AIM2A) and experimental model of IG alcohol feeding in mice (AIM1A). In particular, if a specific transcription factor, such as NF-1, is critical in both human and mouse aHSCs (AIM2B), we can then directly test its role in vivo by selectively knocking out the gene in a conditional knockout mouse subjected to alcohol-induced liver fibrosis (AIM1B). By carefully comparing human and mouse alcohol-induced liver fibrosis and the concomitant activation of hepatic stellate cells, we can translate the results of our mouse studies into the human disease.